Sevoflurane Aggravates the Progress of Alzheimer’s Disease Through NLRP3/Caspase-1/Gasdermin D Pathway
Background: Alzheimer’s disease (AD) is the most common form of dementia worldwide. Previous studies have reported that sevoflurane, a frequently used anesthetic, can induce cognitive impairment in preclinical and clinical settings. However, the mechanism underlying the development of this neurotoxi...
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Frontiers Media S.A.
2022-01-01
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| Series: | Frontiers in Cell and Developmental Biology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcell.2021.801422/full |
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| author | Di Tian Di Tian Di Tian Yanmei Xing Yanmei Xing Yanmei Xing Wenli Gao Wenli Gao Wenli Gao Hongyan Zhang Hongyan Zhang Yifeng Song Yifeng Song Ya Tian Ya Tian Zhongliang Dai Zhongliang Dai Zhongliang Dai |
| author_facet | Di Tian Di Tian Di Tian Yanmei Xing Yanmei Xing Yanmei Xing Wenli Gao Wenli Gao Wenli Gao Hongyan Zhang Hongyan Zhang Yifeng Song Yifeng Song Ya Tian Ya Tian Zhongliang Dai Zhongliang Dai Zhongliang Dai |
| author_sort | Di Tian |
| collection | DOAJ |
| description | Background: Alzheimer’s disease (AD) is the most common form of dementia worldwide. Previous studies have reported that sevoflurane, a frequently used anesthetic, can induce cognitive impairment in preclinical and clinical settings. However, the mechanism underlying the development of this neurotoxicity is currently unclear.Methods: Seven-month-old APP/PS1 mice were placed in an anesthesia induction box containing 3% sevoflurane in 100% O2 for 6 h, while BV2 cells were cultured with 4% sevoflurane for 6 h. Pyroptosis and tau protein expression in excised hippocampus tissues and cells were measured using Western blotting and immunofluorescence assay. Caspase-1 and NLRP3 were knocked out in BV2 microglia using CRISPR/Cas9 technology to determine whether they mediate the effects induced by sevoflurane.Results: Sevoflurane directly activated caspase-1 to induce pyroptosis in the mouse model of AD via NLRP3 and AIM2 activation. In addition, sevoflurane mediated cleavage of gasdermin D (GSDMD) but not gasdermin E (GSDME), promoted the biosynthesis of downstream interleukin-1β and interleukin-18, and increased β-amyloid (Aβ) deposition and tau phosphorylation. The nontoxic caspase-1 small-molecule inhibitor VX-765 significantly inhibited this activation process in microglia, while NLRP3 deletion suppressed sevoflurane-induced caspase-1 cleavage and subsequently pyroptosis, as well as tau pathology. Furthermore, silencing caspase-1 alleviated the sevoflurane-induced release of IL-1β and IL-18 and inhibited tau-related enzymes in microglia.Conclusion: This study is the first to report that clinical doses of sevoflurane aggravate the progression of AD via the NLRP3/caspase-1/GSDMD axis. Collectively, our findings elucidate the crucial mechanisms of NLRP3/caspase-1 in pyroptosis and tau pathogenesis induced by sevoflurane and suggest that VX-765 could represent a novel therapeutic intervention for treating AD. |
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| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-23T19:02:11Z |
| publishDate | 2022-01-01 |
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| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-f37e7141affc4eedbc8ded28061ccb5c2022-12-21T17:34:42ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2022-01-01910.3389/fcell.2021.801422801422Sevoflurane Aggravates the Progress of Alzheimer’s Disease Through NLRP3/Caspase-1/Gasdermin D PathwayDi Tian0Di Tian1Di Tian2Yanmei Xing3Yanmei Xing4Yanmei Xing5Wenli Gao6Wenli Gao7Wenli Gao8Hongyan Zhang9Hongyan Zhang10Yifeng Song11Yifeng Song12Ya Tian13Ya Tian14Zhongliang Dai15Zhongliang Dai16Zhongliang Dai17Department of Anesthesiology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, ChinaDepartment of Anesthesiology, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, ChinaShenzhen Engineering Research Center of Anesthesiology, Shenzhen, ChinaDepartment of Anesthesiology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, ChinaDepartment of Anesthesiology, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, ChinaShenzhen Engineering Research Center of Anesthesiology, Shenzhen, ChinaDepartment of Anesthesiology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, ChinaDepartment of Anesthesiology, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, ChinaShenzhen Engineering Research Center of Anesthesiology, Shenzhen, ChinaDepartment of Anesthesiology, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, ChinaShenzhen Engineering Research Center of Anesthesiology, Shenzhen, ChinaDepartment of Anesthesiology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, ChinaShenzhen Engineering Research Center of Anesthesiology, Shenzhen, ChinaDepartment of Anesthesiology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, ChinaShenzhen Engineering Research Center of Anesthesiology, Shenzhen, ChinaDepartment of Anesthesiology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, ChinaDepartment of Anesthesiology, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, ChinaShenzhen Engineering Research Center of Anesthesiology, Shenzhen, ChinaBackground: Alzheimer’s disease (AD) is the most common form of dementia worldwide. Previous studies have reported that sevoflurane, a frequently used anesthetic, can induce cognitive impairment in preclinical and clinical settings. However, the mechanism underlying the development of this neurotoxicity is currently unclear.Methods: Seven-month-old APP/PS1 mice were placed in an anesthesia induction box containing 3% sevoflurane in 100% O2 for 6 h, while BV2 cells were cultured with 4% sevoflurane for 6 h. Pyroptosis and tau protein expression in excised hippocampus tissues and cells were measured using Western blotting and immunofluorescence assay. Caspase-1 and NLRP3 were knocked out in BV2 microglia using CRISPR/Cas9 technology to determine whether they mediate the effects induced by sevoflurane.Results: Sevoflurane directly activated caspase-1 to induce pyroptosis in the mouse model of AD via NLRP3 and AIM2 activation. In addition, sevoflurane mediated cleavage of gasdermin D (GSDMD) but not gasdermin E (GSDME), promoted the biosynthesis of downstream interleukin-1β and interleukin-18, and increased β-amyloid (Aβ) deposition and tau phosphorylation. The nontoxic caspase-1 small-molecule inhibitor VX-765 significantly inhibited this activation process in microglia, while NLRP3 deletion suppressed sevoflurane-induced caspase-1 cleavage and subsequently pyroptosis, as well as tau pathology. Furthermore, silencing caspase-1 alleviated the sevoflurane-induced release of IL-1β and IL-18 and inhibited tau-related enzymes in microglia.Conclusion: This study is the first to report that clinical doses of sevoflurane aggravate the progression of AD via the NLRP3/caspase-1/GSDMD axis. Collectively, our findings elucidate the crucial mechanisms of NLRP3/caspase-1 in pyroptosis and tau pathogenesis induced by sevoflurane and suggest that VX-765 could represent a novel therapeutic intervention for treating AD.https://www.frontiersin.org/articles/10.3389/fcell.2021.801422/fullgasdermin Dpyroptosissevofluranetau pathologyVX-765 |
| spellingShingle | Di Tian Di Tian Di Tian Yanmei Xing Yanmei Xing Yanmei Xing Wenli Gao Wenli Gao Wenli Gao Hongyan Zhang Hongyan Zhang Yifeng Song Yifeng Song Ya Tian Ya Tian Zhongliang Dai Zhongliang Dai Zhongliang Dai Sevoflurane Aggravates the Progress of Alzheimer’s Disease Through NLRP3/Caspase-1/Gasdermin D Pathway Frontiers in Cell and Developmental Biology gasdermin D pyroptosis sevoflurane tau pathology VX-765 |
| title | Sevoflurane Aggravates the Progress of Alzheimer’s Disease Through NLRP3/Caspase-1/Gasdermin D Pathway |
| title_full | Sevoflurane Aggravates the Progress of Alzheimer’s Disease Through NLRP3/Caspase-1/Gasdermin D Pathway |
| title_fullStr | Sevoflurane Aggravates the Progress of Alzheimer’s Disease Through NLRP3/Caspase-1/Gasdermin D Pathway |
| title_full_unstemmed | Sevoflurane Aggravates the Progress of Alzheimer’s Disease Through NLRP3/Caspase-1/Gasdermin D Pathway |
| title_short | Sevoflurane Aggravates the Progress of Alzheimer’s Disease Through NLRP3/Caspase-1/Gasdermin D Pathway |
| title_sort | sevoflurane aggravates the progress of alzheimer s disease through nlrp3 caspase 1 gasdermin d pathway |
| topic | gasdermin D pyroptosis sevoflurane tau pathology VX-765 |
| url | https://www.frontiersin.org/articles/10.3389/fcell.2021.801422/full |
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